The primary objective is to study the effects of environmental lead exposures and allelic variants of the vitamin D receptor (VDR) gene on the development of osteoporosis in middle-aged women. The study will be conducted as a prospective evaluation of three major hypotheses: (1) Lead exposure is associated with declines in bone mineral density (BMD) and increases in bone turnover (defined by serum osteocalcin and urinary cross-linked N telopeptide of type I collagen or NTX) in middle-aged women. (2) Specific restriction fragment length polymorphisms within the VDR gene defined by the endonucleases Bsml and Taql are associated with declines in BMD and increases in bone turnover. (3) Lead exposure modifies the effects of VDR genotype on the determination of changes in both BMD and bone turnover. The study is designed to use information collected through two ongoing studies: the Nurses' Health Study(NHS), an established longitudinal investigation of chronic disease in female registered nurses, and an NIEHS R01-ES05257 supported evaluation of lead exposure and cognitive and renal function in middle-aged adults that includes large sample of NHS participants. As part of this ongoing research, two measures of BMD at the lumbar spine and hip (measured 4 or 5 years apart) and information regarding bone lead levels, blood lead levels, diet , medication use, hormone use, reproductive history, fracture and medical history will be available for 427 NHS participants. The current proposal includes laboratory analyses of archived biological specimens from these 427 women for assessment of VDR genotype, serum osteocalcin, and urine NTX. Results of preliminary studies include findings of: (1) cross-sectional inverse associations of bone lead levels with BMD, and (2) cross-sectional positive associations of both blood and bone lead with urine NTX in a subsample of the first 302 women studied to date. These results provide initial support for the hypothesis that increased bone lead levels are associated with prospective decreases in BMD and increased bone turnover activity. BMD is a critical risk factor for osteoporosis and osteoporotic fractures, which are associated with annual cost of 18 billion and pose the same estimated lifetime risk of death (in women) as does breast cancer. Evaluating potential environmental risk factors for osteoporosis, corroborating results of recent studies of the genetics of this disease, and achieving and understanding of possible gene-environment interactions related to the development of this disorder are of great public health importance as a means for identifying appropriate strategies for osteoporosis treatment and prevention.